General formalism for the application of explicitly correlated Gaussian-type basis functions for nonadiabatic calculations on many-body systems is presented. In this approach the motions of all particles (electrons and nuclei) are correlated at the same time. The energy associated with the external degrees of freedom, i.e., the motion of the center-of-mass, is eliminated in an effective way from the total energy of the system. Methodology for construction of the many-body nonadiabatic wave function and algorithms for evaluation of the multicenter and multiparticle integrals involving explicity correlated Gaussian cluster functions are derived and computationally implemented. Then analytical derivation of multi-center and multi-particle integrals for explicitly correlated Cartesian Gaussian-type cluster functions is demonstrated. The evaluation method is based on application of raising operators which transform spherical cluster Gaussian functions into Cartesian Gaussian functions. Next, the Newton-Raphson procedure for optimization of the non-linear parameters (Gaussian exponents) appearing in the Gaussian-type cluster functions is developed. The procedure employs the first and second analytical derivatives of the variational functional with respect to the Gaussian exponents. The computational implementation of Newton-Raphson optimization procedure is described and some numerical calculations are presented. Finally, the methodology for generating higher nonadiabatic rotational states is presented.

High resolution microwave spectra for the transition metal compounds cobalt tri-carbonyl nitrosyl (Co(CO)₃NO), cyclopentadienyl cobalt di-carbonyl (CpCo(CO)₂), and cyclopentadienyl manganese tri-carbonyl (CpMn(CO)₃) were obtained for the first time using pulsed beam Fourier transform spectroscopy. An oblate symmetric top spectrum was measured for Co(CO)₃NO and the first gas phase value of the cobalt nuclear quadrupole coupling parameter was obtained. The asymmetric top hindered rotor spectrum for CpCo(CO)₂ was measured and a barrier to internal rotation was estimated from the spectrum. Analysis of the prolate symmetric top hyperfine spectrum of CpMn(CO)₃ yielded the first gas phase measurement of the rotational constant and the Mn nuclear quadrupole coupling. High resolution microwave spectra for the iron containing transition metal complexes cyclobutadiene iron tri-carbonyl (CbFe(CO)₃), cyclohexadiene iron tri-carbonyl (C-hexFe(CO)₃) were obtained and a Kraitchman analysis of the isotopic substitution data for the butadiene iron tri-carbonyl (BuFe(CO)₃) is also discussed. Structural parameters for the HCCH-CO were obtained from the various isotopomers for this complex. An analysis of the distortion parameter D(J) yielded an estimation of the binding energy for this weakly bound complex. Analysis of spectra for nitrosyl chloride (NOCl) and chlorine tri-fluoride (ClF₃) yielded the first high resolution low J data sets for these molecules. The quadrupole coupling data are interpreted using the Townes-Dailey model for quadrupole coupling and an improved ground state structure for ClF₃ was obtained. Microwave spectra reported here were obtained using a pulsed beam Fourier transform microwave spectrometer constructed at the University of Arizona. The design is similar to original Flygare-Balle apparatus with many modifications for improving signal sensitivity and data acquisition.

Part A. Vibronic transitions of rhodium monoxide (Rh¹⁶O and Rh¹⁸O) were observed in the 380 to 700 nm region. Laser-induced fluorescence identified two ²[pi]r - X⁴Σ⁻ progressions with origins at {15 667, 15 976} and {15 874, 16 167} cm⁻¹. These progressions were labeled [15.8] ²[pi] - X⁴Σ⁻ and [16.0] ²[pi] - X⁴Σ⁻, respectively. Vibrational parameters were determined for the ground and excited states... Part B. Density functional and configuration interaction calculations on the lowest singlet and triplet potential energy surfaces of hydrogen, fluorine, and chlorine azide for the reactions XN₃ (~X¹A¹) -- NX(X³Σ; a¹Δ) + N₂ (X¹Σ⁺g) and XN₃ -- X(X²S; X²P₃/₂) + N₃(X²[pi]g) (X = H, F, Cl) show that the lowest energy dissociation pathway proceeds exothermically to NX(a) + N₂ . This surface is crossed on the bound singlet region by a dissociative triplet surface. Unimolecular decomposition rates for each pathway and the branching ratio support the experimental observations: HN₃ dissociates to ground state products while FN₃ and CIN₃ produce significant amounts of electronically excited NX. / Graduate

This dissertation describes new computational approaches at high resolution for practical structure-based drug discovery. It begins with a brief review of structure-based computational approaches for drug discovery in comparison with ligand-based ones, followed by a discussion of important applications in selecting drug-like compounds and predicting drug metabolites. Since three-dimensional target structures are crucial for structure-based drug discovery, a new methodology based on force fields for protein structure refinement was developed. This methodology employs the VSGB 2.0 energy model in combination with a robust protonation state assignment algorithm and efficient sampling strategies. High accuracy was obtained for predicting 2239 protein side chains and 115 14-20 residue loops. Given the precision and uniform robustness, this methodology is believed for the first time to be suitable to tackle practical problems in structure-based drug discovery. The VSGB 2.0 energy model was then applied in the development of a new accurate approach (IDSite) for predicting P450-mediated drug metabolism, a problem of great practical interest for drug discovery. IDSite is able to efficiently model induced-fit effects using flexible docking and constrained refinements. Sites of metabolism are determined based on the physical interactions between a P450 enzyme and the ligand. Preliminary tests with 56 compounds displayed both low false positive and low false negative rates, which demonstrate the high potential of IDSite to be used in metabolism tests for drug discovery. In conclusion, this dissertation presents new computational approaches at high resolution to problems related to structure-based drug discovery with unprecedented accuracy. Given such high accuracy, these approaches are very promising in addressing practical issues in pharmaceutical research and development, and in enhancing our capability in the search for new safe drugs.

This thesis describes spectroscopic studies of three different systems: silver nanoparticles, the dye molecule rhodamine 6G adsorbed on graphene, and the type IV pili and c-type cytochromes produced by the dissimilatory metal-reducing bacterium Geobacter sulfurreducens. Although these systems are quite different in some ways, they can all be considered examples of nanomaterials. A nanomaterial is generally defined as having at least one dimension below 100 nm in size. Silver nanoparticles, with sub-100 nm size in all dimensions, are examples of zero-dimensional nanomaterials. Graphene, a single atomic layer of carbon atoms, is the paradigmatic two-dimensional nanomaterial. And although bacterial cells are on the order of 1 µm in size, the type IV pili and multiheme c-type cytochromes produced by G. sulfurreducens can be considered to be one- and zero-dimensional nanomaterials respectively. A further connection between these systems is their strong interaction with visible light, allowing us to study them using similar spectroscopic tools. The first chapter of this thesis describes research on the plasmon-mediated photochemistry of silver nanoparticles. Silver nanoparticles support coherent electron oscillations, known as localized surface plasmons, at resonance frequencies that depend on the particle size and shape and the local dielectric environment. Nanoparticle absorption and scattering cross-sections are maximized at surface plasmon resonance frequencies, and the electromagnetic field is amplified near the particle surface. Plasmonic effects can enhance the photochemistry of silver particles alone or in conjunction with semiconductors according to several mechanisms. We study the photooxidation of citrate by silver nanoparticles in a photoelectrochemical cell, focusing on the wavelength-dependence of the reaction rate and the role of the semiconductor substrate. We find that the citrate photooxidation rate does not track the plasmon resonance of the silver nanoparticles but instead rises monotonically with photon energy. These results are discussed in terms of plasmonic enhancement mechanisms and a theoretical model describing hot carrier photochemistry. The second chapter explores the electronic absorption and resonance Raman scattering of the dye molecule rhodamine 6G (R6G) adsorbed on graphene. Graphene has been shown to quench the fluorescence of adsorbed molecules and quantum dots, and some previous studies have reported that the Raman scattering from molecules adsorbed on graphene is enhanced. We show that reflective contrast spectroscopy can be used to obtain the electronic absorption spectrum of R6G adsorbed on graphene, allowing us to estimate the surface concentration of the dye molecule. From these results we are able to calculate the absolute Raman scattering cross-section for R6G adsorbed on bilayer graphene. We find that there is no evidence of enhancement but instead that the cross-section is reduced by more than three-fold from its value in solution. We further show that a model incorporating electromagnetic interference effects can reproduce the observed dependence of the R6G Raman intensity on the number of graphene layers. The third and final chapter describes the preliminary results from studies of the dissimilatory metal-reducing bacterium Geobacter sulfurreducens. This anaerobic bacterium couples the oxidation of organic carbon sources to the reduction of iron oxides and other extracellular electron acceptors, a type of anaerobic respiration that necessitates an electron transport chain that can move electrons from the interior of the cell to the extracellular environment. The electron transport chain in G. sulfurreducens has not been completely characterized and two competing mechanisms for the charge transport have been proposed. The first holds that G. sulfurreducens produces type IV pili, protein filaments several nanometers in width, with intrinsic metallic-like conductivity. According to this mechanism, the conductive pili mediate electron transport to extracellular acceptors. The second proposed mechanism is that charge transport proceeds by electron hopping between the heme groups in the many c-type cytochromes produced by G. sulfurreducens. In this picture, the observed conductivity of the pili is due to hopping through associated cytochrome proteins. Our aim is to explore these alternative mechanisms for electron transport in G. sulfurreducens through electrical and optical studies. We report the work we have done thus far to culture and characterize G. sulfurreducens, and we show that preliminary micro-Raman studies of G. sulfurreducens cells confirm that we can detect the spectroscopic signature of c-type cytochrome proteins. Future directions for this ongoing work are briefly discussed.

The internal DNA of the Pf1 bacteriophage is known from its dimensions to be the most extended naturally occurring DNA. Understanding its conformation is critical to further insights about DNA stability and packing processes in Pf1 and similar filamentous phages, and is of broader interest to biophysical studies of DNA. Structural studies of the intact 36 MDa Pf1 bacteriophage by solid-state NMR have, from their inception, been remarkably ambitious undertakings due to the size of the system and its structural complexity. Assignment and structural characterization of the major coat protein have been aided by symmetry and abundance of signal, and have been remarkably successful. However, it is only with the advent of improvements in methodology that the DNA of Pf1 can be studied. Recent rapid advances in techniques such as dynamic nuclear polarization have greatly improved sensitivity and made solid-state NMR studies applicable to a broader range of biopolymers and biological assemblies. The first high-resolution NMR study of the Pf1 DNA is presented herein. Assignment of the 13C and 15N resonances of the DNA at the level of nucleotide type has revealed a number of unusual chemical shifts, at or beyond the edges of their respective ranges in available databases. These database comparisons, especially at key conformational reporter sites such as sugar C3' and C5', confirm important details of existing structural models, such as a C2'-endo/gauche sugar pucker, anti glycosidic angle, an overall lack of base pairing, and the presence of aromatic stacking. Specific protein-DNA contacts consistent with those predicted by models are also observed.Fragment-based ab initio chemical shift prediction methods are employed in efforts to derive additional information from the experimental chemical shifts. The Pf1 DNA is found to be most consistent with models of highly stretched P-DNA derived from DNA stretching experiments, in contrast to more conventional forms like A- or Z-DNA. Further, the goodness-of-fit of existing structural models as well as several novel models is assessed; it is found that one of the new models, "Hybrid/2XKM", created by combining recent highly refined DNA and coat protein models, best reproduces experimental chemical shift patterns, and should likely be used as a starting point for subsequent refinements. Similar methodology is applied to the selectivity filter of the S. lividans potassium ion channel KcsA, finding that changes in ion occupancy alone are insufficient to reproduce experimental chemical shift perturbations. Hydration is important to the environment of the Pf1 DNA, and to our ability to detect it. NMR investigation of water populations in Pf1 samples reveals that water is in contact with a number of buried protein residues and the internal DNA, making a strong case for the existence of a pool of "internal hydration water." Such a water population has great potential to further benefit solid-state NMR studies of the Pf1 bacteriophage. Also, a new tool to study, analyze, and predict the effects of crystal contacts on solid-state NMR spectra is presented, along with a discussion of isotopic labeling strategies to reduce spectral congestion and aid in the collection of structural restraints for complex biomolecular assemblies.

This dissertation presents multi-photon spectroscopic studies on molecule/metal interfaces and graphene. Two different aspects of these ultrathin molecular or atomic materials were investigated: (1) the electronic structure of molecule/metal interfaces and (2) nonlinear optical properties of graphene. For the case (1), two-photon photoemission (TPPE) using a femotosecond laser was employed to investigate occupied and unoccupied electronic states of molecule/metal interfaces. Here we selected two specific examples of interfaces, benzenethiols on Cu(111) and hexa-cata-hexabenzocoronene (HBC) on Cu(111), which are important model systems for an organic / electrode interface of organic semiconductor devices. Although the same copper substrate was used for all the experiments, the nature of interfaces was strongly affected by the interaction between molecular adlayers and metal substrate. Our TPPE measurements on two benzenthiol species, thiophenol and p-fluorothiophenol, on Cu(111) focus on the role of adsorbates in shifting surface polarization and effecting surface electron confinement. As the coverage of each molecule increases, their photoemission-measured work functions exhibit nearly identical behavior up to 0.4-0.5 ML, at which point their behavior diverges; this behavior can be fit to an interfacial bond model for the surface dipole. In addition, our results show the emergence of an interfacial electronic state 0.1-0.2 eV below the Fermi level. This electronic state is attributed to quantum-mechanical-confinement shifting of the Cu(111) surface state by the molecular adsorbates. Another TPPE study of ours was carried out on an organic semiconductor, HBC, deposited on Cu(111). An increase of HBC coverage continuously shifts the vacuum level of the Cu substrate until a coverage of 2 ML is reached. In the same range of coverage, the Shockley state and the image potential states are quenched while new unoccupied states develop. The momentum- and polarization-resolved photoemission spectra reveal that the new states are originated from a Cu image state. Electron localization is discussed with respect to the structural evolution of HBC. For the case (2), nonlinear optical scanning microscopy was designed to study third-harmonic generation (THG) from micron- scale graphene crystals on glass substrate. The polarization-, thickness-, and orientation- dependence of THG signals from the graphene were measured and compared to theoretical prediction using the nonlinear optical slab model of Bloembergen and Pershan. The results revealed in-plane isotropy and out-of-plane anisotropy of the THG signals and sub-quadratic dependence of the layer number. Due to the strong THG signal, background-free imaging of graphene crystal was carried out. This result implies the potential application of THG for imaging graphene on arbitrary substrates.

Recent discoveries of highly efficient solar cells based on methylammonium lead iodide (MAPbI3) perovskites (three dimensional, 3D, structure) attract a surge in research activity on the photo-generated carriers and how carrier and/or exciton interact in these materials. Understanding the photo-carrier dynamics and interactions as well as the nature of the trap states are crucial for elucidating the working mechanisms of perovskite solar cells. Lead iodide perovskites can also be prepared in two-dimensional (2D) structures, which are essentially self-assembled quantum wells. Questions remain on whether the photo-excited species are free carriers or excitons and how they interact and recombine. The nature of trap states and how to minimized them in these materials are also unclear. In this thesis, the carrier/ exciton interactions and the trap states in 3D and 2D lead iodide perovskites and the Auger recombination in 3D perovskites are studied with ultrafast Time-Resolved Transient Absorption (TA) Spectroscopy. The first part of this thesis is the carrier generation and carrier/carrier interaction study in 3D MAPbI3 along with a comparative study on the exciton/carrier interaction in 2-dimentional (2D) lead iodide perovskites (Chapter 4 and 5). The major photo-generated species are charge carriers in 3D perovskites and excitons in 2D perovskites. Upon high photon energy excitation, the hot electrons and holes are created instantaneously which induce a red-shift on the band-edge optical transition in 3D perovskites while a broadening effect on the 1S exciton in 2D perovskites. The red-shift is the result of the Stark effect from the hot carriers and the broadening comes from the scattering by the carriers. The band-edge carriers in 3D perovskite recombine following two-molecular recombination at low density and Auger recombination at higher density. In 2D perovskite, we observed a blue-shift in 1S exciton transition due to the localized exciton-exciton interaction. The 6th chapter is the discussion on the below-gap trap states, depending on the dimensionality and the organic/inorganic interfaces. We observed trap states in both 3D and 2D perovskites below the optical band-gap, and in 2D perovskites the trap states increase with the decrease of the quantum well thickness. With the help of surface sensitive UPS and temperature dependent PL measurements, we concluded the trap states localize at the “soft” organic/inorganic interfaces, which in 3D are the grain boundaries and surfaces and in 2D are the barrier/well interfaces. Aside from the TA studies on perovskites, Time-Resolved Second Harmonic Generation (TR-SHG) study on the transient electric field in neat C70 film and CuPc/C70 bilayer film are reported at the end of the thesis. TR-SHG has been applied to study the interfacial electric field generation at donor/acceptor interface but the total SHG signal may have contributions from the donor, the acceptor and the interface. All of these contributions need to be considered in order to fully understand the TR-SHG signal. With ultrafast laser excitation with ~100 fs time scale, we observed an internal E-field generated in C70 film due to charge drift and diffusion, with ~ 10 ps rise time. For CuPc/C70 bilayer film, an additional interfacial E-field appears with a time constant of ~0.1 ps due to charge separation at the donor/acceptor interface. The E-Field induced SHG signal from these two E-fields interfere with each other giving rise to the overall SHG, which is dependent on both the probe polarization and the film thickness.

Nonlinear optical microscopy (NOM) has become increasingly popular in biomedical research in recent years with the developments of laser sources, contrast mechanisms, novel probes and etc. One of the advantages of NOM over the linear counterpart is the ability to image deep into scattering tissues or even on the whole animals. This is due to the adoption of near-infrared excitation that is of less scattering than visible excitation, and the intrinsic optical sectioning capability minimizing the excitation background beyond focal volume. Such an advantage is particularly prominent in two-photon fluorescence microscopy compared to one-photon fluorescence microscopy. In addition, NOM may provide extra molecular information (e.g. second harmonic generation and third harmonic generation) or stronger signal (e.g. stimulated Raman scattering and coherent anti-Stokes Raman scattering compared to spontaneous Raman scattering), because of the nonlinear interaction between strong optical fields and molecules. However, the merits of NOM are not yet fully exploited to tackle important questions in biomedical research. This thesis contributes to the developments of NOM in two aspects that correspond to two fundamental problems in biomedical imaging: first, how to non invasively image small functional biomolecules in live biological systems (Chapters 1-4); second, how to extend the optical imaging depth inside scattering tissues (Chapters 5-6). The ability to non-perturbatively image vital small biomolecules is crucial for understanding the complex functions of biological systems. However, it has proven to be highly challenging with the prevailing method of fluorescence microscopy. Because it requires the utilization of large-size fluorophore tagging (e.g., the Green Fluorescent Protein tagging) that would severely perturb the natural functions of small bio-molecules. Hence, we devise and construct a nonlinear Raman imaging platform, with the coupling of the emerging stimulated Raman scattering (SRS) microscopy and tiny vibrational tags, which provides superb sensitivity, specificity and biocompatibility for imaging small biomolecules (Chapters 1-4). Chapter 1 outlines the theoretical background for Raman scattering. Chapter 2 describes the instrumentation for SRS microscopy, followed with an overview of recent technical developments. Chapter 3 depicts the coupling of SRS microscopy with small alkyne tags (C≡C) to sensitively and specifically image a broad spectrum of small and functionally vital biomolecules (i.e. nucleic acids, amino acids, choline, fatty acids and small molecule drugs) in live cells, tissues and animals. Chapter 4 reports the combination of SRS microscopy with small carbon-deuterium (C-D) bonds to probe the complex and dynamic protein metabolism, including protein synthesis, degradation and trafficking, with subcellular resolution through metabolic labeling. It is to my belief that the coupling of SRS microscopy with alkyne or C-D tags will be readily applied in answering key biological questions in the near future. The remaining chapters of this thesis (Chapters 5-6) present the super-nonlinear fluorescence microscopy (SNFM) techniques for extending the optical imaging depth into scattering tissues. Unlike SRS microscopy that is an emerging technique, multiphoton microscopy (mainly referred as two-photon fluorescence microscopy), has matured over 20 years with its setup scheme and biological applications. Although it offers the deepest penetration in the optical microscopy, it still poses a fundamental depth limit set by the signal-to-background ratio when imaging into scattering tissues. Three SNFM techniques are proposed to extend such a depth limit: unlike the conventional multiphoton microscopy whose nonlinearity stems from virtual-states mediated simultaneous interactions between the incident photons and the molecules, the high-order nonlinearity of the SNFM techniques that we have conceived is generated through real-state mediated population-transfer kinetics. In particular, Chapter 5 demonstrates the multiphoton activation and imaging (MPAI) microscopy, which adopts a new class of fluorophores, the photoactivatable fluorophores, to significantly extend the fundamental imaging depth limit. Chapter 6 theoretically and analytically depicts two additional SNFM techniques of stimulated emission reduced fluorescence (SERF) microscopy and focal saturation microscopy. Both MPAI and focal saturation microscopies exhibit a fourth order power dependence, which is effectively a four-photon process. SERF presents a third order power dependence for a three-photon process.

This dissertation explores the electronic characteristics of silicon at the single molecule level. This idea is born as we enter the post-Moore’s law era when the exponential shrinking of conventional silicon microelectronics has begun to stall and an investigation of molecular materials is timely. Single-molecule electronic components have shown promising functionalities such as conductors, switches, and diodes, and single molecule junctions have become a widely used test-bed for probing electron transport properties at the molecular level. In this thesis, we use scanning tunneling microscope break junction method to create single molecule junctions with a variety of silicon molecular wires. Our results demonstrate electronic properties of silicon beyond it being a semiconductor in its bulk form. We begin this work in pursuit of an expanded understanding of low-k dielectric components with an experimental goal on determining the cause of its breakdown. Low-k dielectrics are beneficial as they enable faster switching speeds and lower heat dissipation, however, they tend to breakdown after prolonged usage under an applied voltage. At the atomic level, low-k dielectric breakdown involves bond rupture. To determine which bond breaks easily, we conduct experimental studies on the robustness of individual chemical bonds that are commonly found in low-k dielectrics. We subject the single molecule junctions to a high bias and investigate the breakdown phenomenon of individual Si-Si, Ge-Ge, Si-O, and Si-C bonds. Among these, Si-C proved to be significantly more durable than the others. To further prove our hypothesis that the Si-Si bond ruptures under the applied high bias, we design a two-path molecular structure consisting of a Si-Si bond in parallel with a naphthyl group. The broken junction shows conduction through the naphthyl pathway, strongly indicating that the Si-Si bond is breaking. This demonstrates a method for probing the bond cleavage under an electric field and provides insights to the weak links in low-k dielectrics. Next, we study the fundamental charge transport characteristics of single molecule junctions comprised of Si and Ge-based molecular wires, starting with the simplest form - linear atomic chains. We observe a slower decay of conductance with increasing length in the silanes and germanes than in alkanes, indicating that the electronic delocalization in the Si-Si and Ge-Ge -bonds is stronger than that of the well-studied C-C bonds. Furthermore, we demonstrate that this electronic delocalization in the Si-Si and Ge-Ge bonded backbones enables single-molecule conductance switching. This conductance switch, induced by a mechanical modulation, relies on the nature of the terminal groups and constitutes the first example of a stereoelectronic switch. We also study the molecular conductance of these silanes with metal contacts other than Au, which can potentially open up interesting avenues as metal varies in its electronic states and catalytic activities. We find that Ag electrodes enable higher conductance for thiol-terminated silanes than Au or Pt electrodes. The electrical properties of more complex silicon structures - silicon rings - were probed. We choose a five-membered silicon ring as a target system to investigate the effect of isomerism on single molecule conductance. We find that due to the flexibility of the ring, multiple conformations contribute to the spread in the measured conductance for each isomer. This provides us with a starting point to further compare the conductance of a variety of silicon rings. We find that most of the silicon rings are less conductive than their linear counterparts due to the suboptimal backbone conformation for electronic coupling. In particular, destructive quantum interference appears in one of the bicyclic structures and leads to an exceptionally low conductance. This is the first example of a destructive quantum interference feature ever observed experimentally in a π-bonded rather than a σ-bonded system. Finally, we investigate the impact of strain on molecular conductance of silanes. In one case, we introduce the strain using a silacyclobutane ring in the backbone. Unexpectedly, we find that ring strain enables a new Au-silacycle binding mode, resulting in a much higher conductance state. In another molecular design, we choose disilaacenaphthene in the backbone. This strained disilane is found to constitute an example of a direct Si-to-Au contact in single molecule circuits, thereby demonstrating a new binding motif that is valuable for designing high conducting molecular components. Taken together, this body of work provides important knowledge about the transport properties of silicon at the nano-scale, as well as insights on the design of silicon components for nanoelectronics. This work represents one step forward to create functional silicon molecular components.